Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000152.3(GAA):c.2501_2502delCA (p.Thr834Argfs)

CA10605404

286229 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 77174bc5-987b-4b3a-94f0-868d75cd5e60

HGVS expressions

NM_000152.3:c.2501_2502delCA

NM_000152.3(GAA):c.2501_2502delCA (p.Thr834Argfs)

NC_000017.11:g.80118212_80118213del

CM000679.2:g.80118212_80118213del

NC_000017.10:g.78092011_78092012del

CM000679.1:g.78092011_78092012del

NC_000017.9:g.75706606_75706607del

NG_009822.1:g.21657_21658del

NM_000152.3:c.2501_2502del

NM_001079803.1:c.2501_2502del

NM_001079804.1:c.2501_2502del

NM_000152.4:c.2501_2502del

NM_001079803.2:c.2501_2502del

NM_001079804.2:c.2501_2502del

NM_000152.5:c.2501_2502del

NM_001079803.3:c.2501_2502del

NM_001079804.3:c.2501_2502del

ENST00000302262.7:c.2501_2502del

ENST00000390015.7:c.2501_2502del

ENST00000573556.1:n.454_455del

Pathogenic

PM2 PM3_Supporting PP4 PVS1

Evidence Links 4

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.2501_2502delCA (p.Thr834Argfs) is predicted to result in a frameshift causing a premature termination codon, nonsense medicated decay, and lack of GAA gene product, meeting PVS1. The variant has a highest population minor allele frequency of 0.00005794 in the Latino population, meeting PM2. This variant was found in compound heterozygosity with a known pathogenic variant, c.-32-13T>G, in three patients, who all meet the ClinGen LSD VCEP's PP4 criterion (PMID 22958975). The phase not confirmed in any of these patients. Additional patients with this variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 19588081, 29122469), or the in trans data had been counted towards another variant and therefore were not included here to avoid circular logic (c.1933G>A (p.Asp645Asn), (PMID 23601496). The data meet PP4 and PM3_Supporting. There is a ClinVar entry for this variant (Variant ID: 286229; 2 star review status) with three submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.

PM2

This variant has a highest population minor allele frequency of 0.00005794 (Latino) and therefore meets ClinGen LSD VCEP's threshold for PM2 (<0.001).

PM3_Supporting

This variant was found in compound heterozygosity with a known pathogenic variant, c.-32-13T>G, in 3 patients, who all meet the ClinGen LSD VCEP's PP4 criterion (PMID 22958975). The phase not confirmed in any of these patients. Additional patients with this variant have been reported but were not included because residual GAA not provided (PMID: 19588081, 29122469), or the in trans data had been counted towards another variant, and therefore were not included here to avoid circular logic (c.1933G>A (p.Asp645Asn), PMID 23601496). Based on the ClinGen LSD VCEP's guidelines, this data was given a total of 0.5 points which meets PM3_Supporting.

Patient 3, 8, and 9 are compound heterozygotes for c.2501_2502delCA and c.-32-13T>G in GAA, a known pathogenic variant. However, the phase of the variants was not confirmed. These patients also meet the PP4 criterion (0.5 points). PubMed:22958975

Patients 8, 11, and 14 are compound heterozygotes for c.2501_2502delCA and c.377G>A, c.2560C>T, and c.1905C>A, in GAA, respectively. However, the phase of the variants was not confirmed and the patients do not meet PP4 (0 points). PubMed:19588081

One patient with infantile onset Pompde Disease is a compound heterozygote for c.2501_2502delCA and c.546+2_5delTGGG in GAA. However, the phase of the variants was not confirmed and the patient does not meet PP4 (0 points). PubMed:29122469

Subject E is a compound heterozygote for c.2501_2502delCA and c.1933G>A (p.Asp645Asn) in GAA. c.1933G>A (p.Asp645Asn) is pathogenic based on assessment by the ClinGen LSD VCEP. The phase of the variants was not confirmed. This patient also meets the PP4 criterion. However, in trans data from this patient was included in the classification of c.1933G>A (p.Asp645Asn), so no points were awarded to avoid a circular dependency. PubMed:23601496

PP4

Individual with late onset glycogen storage disease type II with <10% normal GAA activity in muscle.

Subjects 3, 8 and 9, who have late-onset Pompe disease, have 5%, 0.7%, and 5.6% normal GAA activity, respectively, in muscle. The activity in muscle (<10% normal) meets the threshold of the ClinGen Storage Disorders VCEP. PubMed:22958975

Subject E has <1% normal GAA activity in either peripheral blood mononuclear cells (PBMC) or dried blood spot (unspecified). The activity (<10% normal in lymphocytes or muscle samples or <30% in fibroblasts) meets the threshold of the ClinGen Storage Disorders VCEP. PubMed:23601496

PVS1

This is a frameshift variant predicted to result in a premature stop codon that is expected to be detected by nonsense mediated decay. Therefore, this variant meets PVS1.

Approved on: 2020-05-05

Published on: 2020-05-28

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